Compounds based on the ergoline ring system: ##STR1## have a suprising variety of pharmaceutical activities. For example, many of the naturally occurring amides of lysergic acid, which is 8.beta.-carboxy-6-methyl-9-ergolene, have valuable and unique pharmacologic properties. The trivial name "ergoline" is given to the above structure and the 9,10-double bonded compound--related to lysergic acid--is called a 9-ergolene rather than a 9,10-didehydroergoline. When the name D-ergoline is used herein in naming specific compounds, the letter "D" indicates that the C-5 carbon atom configuration has the absolute stereochemistry designated as R and that the hydrogen is .beta.--above the plane of the ring system. However, modern usage has tended to omit the "D" on the ground that the newly synthesized ergolines or ergolenes are universally derivatives of natural products such as lysergic acid or elymoclavine, both of which have the R stereochemical --"D" series --configuration and in which the stereochemical integrity at C-5 is maintained during various synthetic procedures. In the ergolines, the C-10 hydrogen is alpha--below the plane of the ring, the C-5 C-10 ring junction being trans. It should be understood that all of the compounds disclosed herein have the R or .beta. stereochemical configuration at C-5, whether or not the specific or generic name is preceded by a "D", and the .alpha. configuration at C-10.
Among the pharmacologically active amides of lysergic acid are included the naturally-occurring oxytoxic alkaloids ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc., synthetic oxytocics such as methergine as well as the synthetic hallucinogen, lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline (dihydrolysergic acid), known generically as the dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves.
Recently, it has been found by Clemens, Semonsky, Meites, and their various co-workers that many ergot-related drugs have activity as prolactin inhibitors. Ergocornine, dihydroergocornine, 2-bromo .alpha.-ergokryptine and D-6-methyl-8-cyanomethylergoline (Semonsky et al U.S. Pat. No. 3,732,231) are examples of such drugs. References embodying some of the newer findings in the field of ergoline and ergolene chemistry include the following: Nagasawa and Meites, Proc. Soc. Exp't'l. Biol. Med., 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971): Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech. Chem. Commun., 33, 577 (1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971); Schaar and Clemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp. Biol. Med., 139, 659-662 (1972), Bach and Kornfeld, Tetrahedron Letters, 3225 (1974) and Sweeney, Clemens, Kornfeld and Poore, 64th Annual Meeting, American Association for Cancer Research, April 1973. Recently issued patents in the field of ergolines or of lysergic acid derivatives include the following: U.S. Pat. No. 3,923,812, U.S. Pat. No. 3,929,796, U.S. Pat. No. 3,944,582, U.S. Pat. No. 3,934,772, U.S. Pat. No. 3,954,988, U.S. Pat. No. 3,957,785, U.S. Pat. No. 3,966,739, U.S. Pat. No. 3,968,111, U.S. Pat. No. 4,001,242. Many other related and older patents can be found in Patent Office Classification Files 260-256.4 and 260-285.5.
U.S. Pat. No. 4,166,182 issued Aug. 28, 1979 (filed Feb. 8, 1978) discloses and claims D-6-n-propyl-8.beta.-methylmercaptomethylergoline, among other compounds. The latter drug has been given the generic name "pergolide" and is presently undergoing clinical trial as a prolactin secretion inhibitor and in the treatment of Parkinsonism.
The use of pergolide, as a prolactin secretion inhibitor or in the treatment of Parkinsonism, is claimed in U.S. Pat. No. 4,180,582. The use of the corresponding 8.alpha. derivative in treating Parkinsonism is claimed in U.S. Pat. No. 4,246,265. 6-Ethyl-(or allyl)-8.beta.-methylthiomethylergolines are claimed in U.S. Pat. No. 4,202,979.
Fuller et al, Life Sci., 24, 375 (1979) discusses the pharmacology of pergolide. The .alpha. adrenergic blocking activity of pergolide is summarized in Table 5, page 381.
6-Methyl-8.beta.-methylthiomethylergolines are disclosed and claimed in U.S. Pat. Nos. 3,959,288 and 3,901,894 respectively as prolactin secretion inhibitors.
Ergolines which carry a C-2 alkylthio substituent are disclosed in several publications incuding Bernardi et al., U.S. Pat. No. 4,382,940 Mongegani et al., U.S. Pat. No. 4,321,361, (I) and 4,282,941 (II) Ferrari et al., U.S. Pat Nos. 4,197,299 (I) and 4,229,450 (II). No example of a (.+-.)-2-alkylthio-1,3,5,6-benz[c,d]indole has been found.
Dopamine D-1 antagonists are not known.